PROJECT SUMMARY Heart disease has been the leading cause of death in this country for over eighty years. Two fundamental drivers of heart failure are architectural remodeling and matrix deposition (fibrosis). Both of which lack targeted interventions for their prevention or reversal underscoring the need to decipher the molecular basis for this maladaptive structural remodeling. Mechanical forces influence cellular architecture throughout the body, especially in blood vessels, muscle and bone. In accordance with these findings we recently demonstrated that myocyte biomechanics is a primary driver of the nature and severity of cardiac structural remodeling. These data led to the development of a computational description of a cardiac myocyte's mechanical state called the tension index, which trumped all other molecular-genetic metrics as a predictor of the heart's architectural phenotype and disease state in mice and inherited cardiomyopathy patients. This new mechanical paradigm holds promise for early prevention and customized mechanical interventions that could reprogram maladaptive growth and geometry back to normal provided the following key questions are resolved: (1) How do the collective actions of fibroblasts and myocytes that regulate mechanical homeostatic feedback mechanisms guide cardiac plasticity; (2) How is mechanical disequilibrium that is associated with cardiac remodeling sensed by fibroblasts and myocytes; and (3) how do mechanical imbalances alter myocyte epigenetic and transcriptional patterns. Using a newly engineered mouse genetics approach that permits the tactical tuning of the heart's mechanical properties, this application will address these questions by testing the central hypothesis that the magnitude and direction of mechanical disequilibrium initiates predictable architectural remodeling that is reversible by balancing intra and extracellular mechanics. This approach overcomes the field's inability to study mechanical relationships in vivo, which will reveal for the first time how coordinated actions and integration of mechanical sources directs cardiac plasticity. Here these mechanical homeostatic feedback mechanisms will be coopted to discover biomarkers of the heart's mechanical state and hence structural remodeling. We anticipate these findings will fulfill the clinically unmet need for a predictive diagnostic tool and preventive strategy for maladaptive fibrotic and architectural remodeling of the heart.